Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progesterone receptor modulators
ATC code: G03XB02
Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator characterised by a tissue-specific partial progesterone antagonist effect.
Ulipristal acetate exerts a direct effect on the endometrium.
Ulipristal acetate exerts a direct action on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis.
When daily administration of a 5 mg dose is commenced during a menstrual cycle most subjects (including patients with myoma) will complete their first menstruation but will not menstruate again until after treatment is stopped. When ulipristal acetate treatment is stopped, menstrual cycles generally resume within 4 weeks.
The direct action on the endometrium results in class-specific changes in histology termed PAEC. Typically, the histological appearance is an inactive and weakly proliferating epithelium associated with asymmetry of stromal and epithelial growth resulting in prominent cystically dilated glands with admixed oestrogen (mitotic) and progestin (secretory) epithelial effects. Such a pattern has been observed in approximately 60% of patients treated with ulipristal acetate for 3 months. These changes are reversible after treatment cessation. These changes should not be confused with endometrial hyperplasia.
About 5% of patients of reproductive age experiencing heavy menstrual bleeding have an endometrial thickness of greater than 16 mm. In about 10-15% of patients treated with ulipristal acetate the endometrium may thicken (> 16 mm) during the first 3-month treatment course. In case of repeated treatment courses, endometrial thickening was less frequently observed (4.9% of patients after second treatment course and 3.5% after fourth treatment course). This thickening disappears after treatment is withdrawn and menstruation occurs. If endometrial thickness persists after return of menstruations during off-treatment periods or beyond 3 months following the end of treatment courses, it may need to be investigated as per usual clinical practice to exclude other underlying conditions.
A daily dose of ulipristal acetate 5 mg inhibits ovulation in the majority of patients as indicated by progesterone levels maintained at around 0.3 ng/ml.
A daily dose of ulipristal acetate 5 mg partially suppresses FSH levels but serum oestradiol levels are maintained in the mid-follicular range in the majority of patients and are similar to levels in patients who received placebo.
Ulipristal acetate does not affect serum levels of TSH, ACTH or prolactin.
The efficacy of fixed doses of ulipristal acetate 5 mg and 10 mg once daily was evaluated in two Phase 3 randomised, double-blind, 13 week studies recruiting patients with very heavy menstrual bleeding associated with uterine fibroids. Study 1 was double-blind placebo controlled. Patients in this study were required to be anaemic at Study entry (Hb < 10.2 g/dl) and all patients were to receive oral iron 80 mg Fe++ in addition to study medicinal product. Study 2 contained the active comparator, leuprorelin 3.75 mg given once per month by intramuscular injection. In Study 2, a double-dummy method was used to maintain the blind. In both studies menstrual blood loss was assessed using the Pictorial Bleeding Assessment Chart (PBAC). A PBAC >100 within the first 8 days of menses is considered to represent excessive menstrual blood loss.
In study 1, a statistically significant difference was observed in reduction in menstrual blood loss in favour of the patients treated with ulipristal acetate compared to placebo (see Table 1 below), resulting in faster and more efficient correction of anaemia than iron alone. Likewise, patients treated with ulipristal acetate had a greater reduction in myoma size, as assessed by MRI.
In study 2, the reduction in menstrual blood loss was comparable for the patients treated with ulipristal acetate and the gonadotrophin releasing hormone-agonist (leuprorelin). Most patients treated with ulipristal acetate stopped bleeding within the first week of treatment (amenorrhea).
The size of the three largest myomas was assessed by ultrasound at the end of treatment (Week 13) and for another 25 weeks without treatment in patients who did not have hysterectomy or myomectomy performed. Myoma size reduction was generally maintained during this follow-up period in patients originally treated with ulipristal acetate but some re-growth occurred in patients treated with leuprorelin.
Table 1. Results of primary and selected secondary efficacy assessments in Phase III studies:
| Parameter | Study 1 | Study 2 | ||||
|---|---|---|---|---|---|---|
| Placebo N=48 | Ulipristal acetate 5 mg/day N=95 | Ulipristal acetate 10 mg/day N=94 | Leuprorelin 3.75 mg/ month N=93 | Ulipristal acetate 5 mg/day N=93 | Ulipristal acetate 10 mg/day N=95 | |
| Menstrual bleeding Median PBAC at baseline Median change at week 13 | 376 -59 | 386 -329 | 330 -326 | 297 -274 | 286 -268 | 271 -268 |
| Patients in amenorrhea at week 13 | 3 (6.3%) | 69 (73.4%)1 | 76 (81.7%)2 | 74 (80.4%) | 70 (75.3%) | 85 (89.5%) |
| Patients whose menstrual bleeding became normal (PBAC<75) at week 13 | 9 (18.8%) | 86 (91.5%)1 | 86 (92.5%)1 | 82 (89.1%) | 84 (90.3%) | 93 (97.9%) |
| Median change in myoma volume from baseline to week 13a | +3.0% | -21.2%3 | -12.3%4 | -53.5% | -35.6% | -42.1% |
a In Study 1, change from baseline in total myoma volume was measured by MRI. In Study 2, change in the volume of the three largest myomas was measured by ultrasound. Bold values in shaded squares indicate that there was a significant difference in the comparisons between ulipristal acetate and the control. These were always in favour of ulipristal acetate.
P values: 1 = <0.001, 2 = 0.037, 3 = <0.002, 4 = <0.006.
The efficacy of repeated treatment courses fixed doses of ulipristal acetate 5 mg or 10 mg once daily was evaluated in two Phase 3 studies assessing up to 4 intermittent 3-month treatment courses in patients with heavy menstrual bleeding associated with uterine fibroids. Study 3 was on open-label study assessing ulipristal acetate 10 mg, where each of the 3-month treatment was followed by 10 days of double-blind treatment with progestin or placebo. Study 4 was a randomized, double-blind clinical study assessing ulipristal acetate 5 or 10 mg.
Studies 3 and 4 showed efficacy in controlling uterine fibroid symptoms (e.g. uterine bleeding) and reducing fibroid size after 2 and 4 courses.
In study 3, treatment efficacy has been shown over > 18 months of repeated intermittent treatment (4 courses of 10 mg once daily), 89.7% of patients were in amenorrhea at the end of the treatment course 4.
In study 4, 61.9% and 72.7% of patients were in amenorrhea at the end of both treatment course 1 and 2 combined (5 mg dose and 10 mg dose, respectively, p=0.032); 48.7% and 60.5% were in amenorrhea at the end of all four treatment courses combined (5 mg dose and 10 mg dose, respectively, p=0.027). At the end of treatment course 4, 158 (69.6%) subjects and 164 (74.5%) subjects were assessed as being in amenorrhea, in the 5 mg dose and 10 mg dose respectively (p=0.290).
Table 2. Results of primary and selected secondary efficacy assessments in long term Phase III studies:
| Parameter | After treatment course 2 (two times 3 months of treatment) | After treatment course 4 (four times 3 months of treatment) | ||||
|---|---|---|---|---|---|---|
| Study 3a | Study 4 | Study 3 | Study 4 | |||
| Patients starting treatment course 2 or 4 | 10 mg/day N=132 | 5 mg/day N=213 | 10 mg/day N=207 | 10 mg/day N=107 | 5 mg/day N=178 | 10 mg/day N=176 |
| Patients in amenorrheab,c | N=131 | N=205 | N=197 | N=107 | N=227 | N=220 |
| 116 (88.5%) | 152 (74.1%) | 162 (82.2%) | 96 (89.7%) | 158 (69.6%) | 164 (74.5%) | |
| Patients with controlled bleedingb,c,d | NA | N=199 | N=191 | NA | N=202 | N=192 |
| 175 (87.9%) | 168 (88.0%) | 148 (73.3%) | 144 (75.0%) | |||
| Median change in myoma volume from baseline | -63.2% | -54.1% | -58.0% | -72.1% | -71.8% | -72.7% |
a Treatment course 2 assessment corresponds to Treatment course 2 plus one menstrual bleeding.
b Patients with missing values were exluded from the analysis.
c N and % include withdrawn patients
d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding (not including days of spotting) during the last 2 months of a treatment course.
In all Phase III studies including repeated intermittent treatment studies, a total of 7 cases of hyperplasia were observed out of 789 patients with adequate biopsies (0.89%). The vast majority spontaneously reversed to normal endometrium after resumption of menstruation during the off-treatment period. The incidence of hyperplasia did not increase with repeated treatment courses, including data on 340 women who received up to 4 courses of ulipristal acetate 5 or 10 mg and limited data of 43 women who received up to 8 courses of ulipristal acetate 10 mg. The observed frequency is in line with control groups and prevalence reported in literature for symptomatic pre-menopausal women of this age group (mean of 40 years).
The European Medicines Agency has waived the obligation to submit the results of studies with Esmya in all subsets of the paediatric population in leiomyoma of uterus (see section 4.2 for information on paediatric use).
Following oral administration of a single dose of 5 or 10 mg, ulipristal acetate is rapidly absorbed, with a Cmax of 23.5 ± 14.2 ng/ml and 50.0 ± 34.4 ng/ml occurring approximately 1 h after ingestion, and with an AUC0-∞ of 61.3 ± 31.7 ng.h/ml and 134.0 ± 83.8 ng.h/ml, respectively. Ulipristal acetate is rapidly transformed into a pharmacologically active metabolite with a Cmax of 9.0 ± 4.4 ng/ml and 20.6 ± 10.9 ng/ml also occurring approximately 1 h after ingestion, and with an AUC0-∞ of 26.0 ± 12.0 ng.h/ml and 63.6 ± 30.1 ng.h/ml respectively.
Administration of ulipristal acetate (30 mg tablet) together with a high-fat breakfast resulted in approximately 45% lower mean Cmax, a delayed tmax (from a median of 0.75 hours to 3 hours) and 25% higher mean AUC0-∞ compared with administration in the fasted state. Similar results were obtained for the active mono-N-demethylated metabolite. This kinetic effect of food is not expected to be of clinical relevance for daily administration of ulipristal acetate tablets.
Ulipristal acetate is highly bound (>98%) to plasma proteins, including albumin, alpha-l-acid glycoprotein, high density lipoprotein and low density lipoprotein.
Ulipristal acetate and its active mono-N-demethylated metabolite are excreted in breast milk with a mean AUCt milk/plasma ratio of 0.74 ± 0.32 for ulipristal acetate.
Ulipristal acetate is readily converted to its mono-N-demethylated and subsequently to its di-N-demethylated metabolites. In vitro data indicate that this is predominantly mediated by the cytochrome P450 3A4 isoform (CYP3A4). The main route of elimination is through faeces and less than 10% is excreted in the urine. The terminal half-life of ulipristal acetate in plasma following a single dose of 5 or 10 mg is estimated to be about 38 hours, with a mean oral clearance (CL/F) of about 100 l/h.
In vitro data indicate that ulipristal acetate and its active metabolite do not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, or induce CYP1A2 at clinically relevant concentrations. Thus administration of ulipristal acetate is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes.
In vitro data indicate that ulipristal acetate and its active metabolite are not P-gp (ABCB1) substrates.
No pharmacokinetic studies with ulipristal acetate have been performed in women with impaired renal or hepatic function. Due to the CYP-mediated metabolism, hepatic impairment is expected to alter the elimination of ulipristal acetate, resulting in increased exposure. Esmya is contraindicated in patients with hepatic disorder (see section 4.3 and 4.4).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.
Most findings in general toxicity studies were related to its action on progesterone receptors (and at higher concentrations on glucocorticoid receptors), with antiprogesterone activity observed at exposures similar to therapeutic levels. In a 39-week study in cynomolgus monkeys, histological changes resembling PAEC were noted at low doses.
Due to its mechanism of action, ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg/kg), guinea pigs and in monkeys. The safety for a human embryo is unknown. At doses which were low enough to maintain gestation in the animal species, no teratogenic potential was observed.
Reproduction studies performed in rats at doses giving exposure in the same range as the human dose have revealed no evidence of impaired fertility due to ulipristal acetate in treated animals or the offspring of treated females.
Carcinogenicity studies (in rats and mice) showed that ulipristal acetate is not carcinogenic.
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